New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro
P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs used against glioblastoma multiforme (GB). Indeed, Pgp is highly expressed in GB stem cells and in the brain-blood barrier (BBB), the peculiar endothelium surrounding the brain. Inhibiting Pgp activity in the BBB and GB is still...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2018-06-01
|
Series: | Molecules |
Subjects: | |
Online Access: | http://www.mdpi.com/1420-3049/23/6/1401 |
id |
doaj-e590f97d13a1430fa187c437db772bb6 |
---|---|
record_format |
Article |
spelling |
doaj-e590f97d13a1430fa187c437db772bb62020-11-25T00:50:51ZengMDPI AGMolecules1420-30492018-06-01236140110.3390/molecules23061401molecules23061401New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in VitroIris Chiara Salaroglio0Elena Gazzano1Joanna Kopecka2Konstantin Chegaev3Costanzo Costamagna4Roberta Fruttero5Stefano Guglielmo6Chiara Riganti7Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino ItalyDepartment of Oncology, University of Torino, via Santena 5/bis, 10126, Torino ItalyDepartment of Oncology, University of Torino, via Santena 5/bis, 10126, Torino ItalyDepartment of Drug Science and Technology, University of Torino, via Pietro Giuria 9, 10125, Torino, ItalyDepartment of Oncology, University of Torino, via Santena 5/bis, 10126, Torino ItalyDepartment of Drug Science and Technology, University of Torino, via Pietro Giuria 9, 10125, Torino, ItalyDepartment of Drug Science and Technology, University of Torino, via Pietro Giuria 9, 10125, Torino, ItalyDepartment of Oncology, University of Torino, via Santena 5/bis, 10126, Torino ItalyP-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs used against glioblastoma multiforme (GB). Indeed, Pgp is highly expressed in GB stem cells and in the brain-blood barrier (BBB), the peculiar endothelium surrounding the brain. Inhibiting Pgp activity in the BBB and GB is still an open challenge. Here, we tested the efficacy of a small library of tetrahydroisoquinoline derivatives with an EC50 for Pgp ≤ 50 nM, in primary human BBB cells and in patient-derived GB samples, from which we isolated differentiated/adherent cells (AC, i.e., Pgp-negative/doxorubicin-sensitive cells) and stem cells (neurospheres, NS, i.e., Pgp-positive/doxorubicin-resistant cells). Three compounds used at 1 nM increased the delivery of doxorubicin, a typical substrate of Pgp, across BBB monolayer, without altering the expression and activity of other transporters. The compounds increased the drug accumulation within NS, restoring doxorubicin-induced necrosis and apoptosis, and reducing cell viability. In co-culture systems, the compounds added to the luminal face of BBB increased the delivery of doxorubicin to NS growing under BBB and rescued the drug’s cytotoxicity. Our work identified new ligands of Pgp active at low nanomolar concentrations. These compounds reduce Pgp activity in BBB and GB and improve in vitro chemotherapy efficacy in this tumor.http://www.mdpi.com/1420-3049/23/6/1401P-glycoproteinglioblastoma multiformebrain-blood barrierdoxorubicin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Iris Chiara Salaroglio Elena Gazzano Joanna Kopecka Konstantin Chegaev Costanzo Costamagna Roberta Fruttero Stefano Guglielmo Chiara Riganti |
spellingShingle |
Iris Chiara Salaroglio Elena Gazzano Joanna Kopecka Konstantin Chegaev Costanzo Costamagna Roberta Fruttero Stefano Guglielmo Chiara Riganti New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro Molecules P-glycoprotein glioblastoma multiforme brain-blood barrier doxorubicin |
author_facet |
Iris Chiara Salaroglio Elena Gazzano Joanna Kopecka Konstantin Chegaev Costanzo Costamagna Roberta Fruttero Stefano Guglielmo Chiara Riganti |
author_sort |
Iris Chiara Salaroglio |
title |
New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro |
title_short |
New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro |
title_full |
New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro |
title_fullStr |
New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro |
title_full_unstemmed |
New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro |
title_sort |
new tetrahydroisoquinoline derivatives overcome pgp activity in brain-blood barrier and glioblastoma multiforme in vitro |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2018-06-01 |
description |
P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs used against glioblastoma multiforme (GB). Indeed, Pgp is highly expressed in GB stem cells and in the brain-blood barrier (BBB), the peculiar endothelium surrounding the brain. Inhibiting Pgp activity in the BBB and GB is still an open challenge. Here, we tested the efficacy of a small library of tetrahydroisoquinoline derivatives with an EC50 for Pgp ≤ 50 nM, in primary human BBB cells and in patient-derived GB samples, from which we isolated differentiated/adherent cells (AC, i.e., Pgp-negative/doxorubicin-sensitive cells) and stem cells (neurospheres, NS, i.e., Pgp-positive/doxorubicin-resistant cells). Three compounds used at 1 nM increased the delivery of doxorubicin, a typical substrate of Pgp, across BBB monolayer, without altering the expression and activity of other transporters. The compounds increased the drug accumulation within NS, restoring doxorubicin-induced necrosis and apoptosis, and reducing cell viability. In co-culture systems, the compounds added to the luminal face of BBB increased the delivery of doxorubicin to NS growing under BBB and rescued the drug’s cytotoxicity. Our work identified new ligands of Pgp active at low nanomolar concentrations. These compounds reduce Pgp activity in BBB and GB and improve in vitro chemotherapy efficacy in this tumor. |
topic |
P-glycoprotein glioblastoma multiforme brain-blood barrier doxorubicin |
url |
http://www.mdpi.com/1420-3049/23/6/1401 |
work_keys_str_mv |
AT irischiarasalaroglio newtetrahydroisoquinolinederivativesovercomepgpactivityinbrainbloodbarrierandglioblastomamultiformeinvitro AT elenagazzano newtetrahydroisoquinolinederivativesovercomepgpactivityinbrainbloodbarrierandglioblastomamultiformeinvitro AT joannakopecka newtetrahydroisoquinolinederivativesovercomepgpactivityinbrainbloodbarrierandglioblastomamultiformeinvitro AT konstantinchegaev newtetrahydroisoquinolinederivativesovercomepgpactivityinbrainbloodbarrierandglioblastomamultiformeinvitro AT costanzocostamagna newtetrahydroisoquinolinederivativesovercomepgpactivityinbrainbloodbarrierandglioblastomamultiformeinvitro AT robertafruttero newtetrahydroisoquinolinederivativesovercomepgpactivityinbrainbloodbarrierandglioblastomamultiformeinvitro AT stefanoguglielmo newtetrahydroisoquinolinederivativesovercomepgpactivityinbrainbloodbarrierandglioblastomamultiformeinvitro AT chiarariganti newtetrahydroisoquinolinederivativesovercomepgpactivityinbrainbloodbarrierandglioblastomamultiformeinvitro |
_version_ |
1725246137771753472 |